Synthesis of novel 2-acetamide-5-phenylthio-1,3,4-thiadiazole-containing phenyl urea derivatives as potential VEGFR-2 inhibitors.
Mahsa ToolabiFatemeh SafariAdileh AyatiParnian FathiSetareh MoghimiSomayeh SalarinejadRoham ForoumadiShima H M E KetabforooshAlireza ForoumadiPublished in: Archiv der Pharmazie (2022)
A novel series of 2-acetamide-5-phenylthio-1,3,4-thiadiazol derivatives containing a phenyl urea warhead were synthesized and evaluated as antiproliferative agents. The cytotoxic activities of the newly synthesized compounds were evaluated toward three human cancer cell lines, including HT-29, A431, and PC3, as well as normal HDF cells, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. The biological results revealed the highest degree of cytotoxic effects for the 4-chloro-containing compound 9e against the A431 cell line. Further assessment by Western blot analysis assay confirmed the induction of apoptosis by compound 9e, with upregulation of Bax and downregulation of Bcl-2 proteins in A431 cancer cells. In addition, compound 9e inhibited the phosphorylation of vascular endothelial growth factor and its receptor (VEGFR-2) in A431 cancer cells while the total level of actin protein was unchanged. These results were confirmed by a three-dimensional cell culture method using the hanging drop technique.
Keyphrases
- vascular endothelial growth factor
- endothelial cells
- induced apoptosis
- cell cycle arrest
- endoplasmic reticulum stress
- signaling pathway
- oxidative stress
- high throughput
- cell death
- cell proliferation
- papillary thyroid
- pi k akt
- poor prognosis
- binding protein
- single cell
- pluripotent stem cells
- induced pluripotent stem cells
- protein kinase
- small molecule
- squamous cell
- squamous cell carcinoma
- climate change
- lymph node metastasis
- amino acid
- risk assessment
- protein protein